Mifepristone for Metabolic Syndrome

The hormone cortisol is a key regulator of metabolism that influences the use of glucose
(sugar) and fat as fuels. Persistently increased cortisol levels, as in Cushing s syndrome,
lead to obesity, type 2 diabetes mellitus and lipid abnormalities including elevated
triglyceride levels and low high-density lipoprotein (HDL) levels. These same disorders are
also present in patients without Cushing s syndrome, suggesting that cortisol may be involved
in their pathogenesis. Mifepristone is a cortisol-like drug that blocks cortisol action in
the body. It can reverse lipid abnormalities, diabetes and obesity in Cushing s syndrome
patients but its effects on these conditions have not been tested in patients without the
syndrome.

The long-term aim of this clinical trial is to evaluate the ability of mifepristone to
reverse or improve glucose intolerance, dyslipidemia, hypertension and weight gain. An
initial 7-day prospective, randomized, placebo-controlled, crossover study is proposed here
to look at the effect of short-term administration of oral mifepristone or placebo on glucose
intolerance. Given that there are no human data available on the effect of mifepristone on
insulin sensitivity, this will be a pilot study of 15 subjects. Data from this study will
then be used to design a larger trial to evaluate long-term effects on blood pressure and
weight, as well as glucose and triglyceride control.

Overweight or obese subjects with abnormal glucose tolerance will undergo each of the two
treatments in a randomized order, including mifepristone by mouth and a look-alike inert
tablet by mouth. Each treatment study will include two or three days of baseline tests that
will be repeated after seven days of treatment. Treatments will be separated by at least six
and no more than eight weeks. The tests will include blood drawing, urine collection,
administration of glucose and insulin by vein, and a cortisol-like material to evaluate the
metabolism of cortisol and a related hormone, corticosterone.

- INCLUSION CRITERIA:

1. Men and women 35 - 70 years of age

2. Subjects will be overweight or obese, with BMI ranging from 25 - 37 kg/m2.

3. Subjects will have either impaired fasting glucose (greater than or equal to 100
mg/dL) or a 2-hour glucose value greater than or equal to 140 mg/dl during an
oral glucose tolerance test (OGTT).

OR

Mild diabetes defined as patients with a Hba1c less than or equal to 7% on no
medications (diet-controlled) or on a stable dose of metformin and no other
hypoglycemic agents for greater than or equal to 3 months before study entry.

4. Willing and able to comply with study requirements.

EXCLUSION CRITERIA:

1. Pregnancy and lactation

2. Diabetes requiring pharmacologic treatment. Diagnosis of diabetes will be based on the
2011 American Diabetes Association guidelines: Hba1c greater than or equal to 6.5%,
fasting plasma glucose greater than or equal to 126 mg/dl, 2-hour glucose greater than
or equal to 200 mg/dl during an OGTT, or a random blood glucose greater than or equal
to 200 mg/dl along with classic symptoms of hyperglycemia (34)

3. Uncontrolled hypertension (blood pressure greater than or equal to 180/110 mmHg)

4. Current unstable medical conditions including clinically significant impaired cardiac
function (Stage III and IV Cardiac failure), cardiac ischemia, severe respiratory
insufficiency requiring oxygen therapy as assessed on history and/or physical exam

5. Liver function tests (ALT, AST) more than 3-times the upper normal limit

6. Severe renal impairment (creatinine clearance < 30 ml/min)

7. Evidence of human immunodeficiency virus (HIV) based on history and physical
examination and/or known positive HIV antibodies

8. Evidence of hepatitis C based on history and physical examination and/or known
positive hepatitis C (HCV) antibody

9. History of hemorrhagic disorders or on anticoagulants

10. History of endometrial cancer, endometrial hyperplasia, unexplained vaginal bleeding,
or endometrial thickness greater than 6 mm

11. Change in dose of lipid-lowering medications (including HMG Co-A inhibitors ,
fibrates, niacin, ezetemibe, and over-the-counter fish oil supplements) within one
month of study entry and during the study period

12. Current administration of medications known to be strong CYP3A4 inhibitors including
ketoconazole, itraconazole, and erythromycin

13. Use of herbal supplements or grapefruit juice within 14 days of study drug initiation

14. Use of medications or dietary supplements that inihibit or induce CYP3A4 activity
within 14 days of study drug initiation

15. Use of oral, injectable, or inhaled glucocorticoids or megestrol in the past six
months

16. Use of estrogen-containing hormone therapy

17. Potential pseudocushing s states: depression or intake of > 2 alcoholic drinks a day.
Subjects will be screened for depression using the well-validated physician health
questionnaire-9 (PHQ-9) with a score cut-off of greater than or equal to 10 for
moderate depression (35).

18. Subjects who are actively dieting or are in a weight loss program

19. Midnight salivary cortisol > 100 ng/dl on two separate occasions

20. Untreated thyroid dysfunction (TSH and Free T4 not within normal range). If abnormal
on screening labs, they will be repeated to confirm that not due to lab error or
non-thyroidal illness.

21. Moderate to severe anemia (hemoglobin < 10 g/dl)

22. Blood donation of more than 500 ml within one month prior to study enrollment

23. Subjects with a prolonged QTc interval on electrocardiogram

24. Unable to give informed consent